Table 3.
Innate and engineered models of cardiac disease
| Model | Class | Disorder | Gene | Mutation | Reference Nos. | Key Phenotypes |
|---|---|---|---|---|---|---|
| Innate | Arrhythmia syndromes | LQT1 | KCNQ1 | R190Q | 197 | Protein trafficking defects |
| Exon 7 del | 171 | ↑FPD and APD in atrial and ventricular CMs | ||||
| LQT2 | KCNH2 | A561T | 184 | Serve ↓ or absence of Ik, (LQT1) or Ik (LQT2) | ||
| 17 | Arrhythmias charactrized by EADs | |||||
| A614V | 110 | ↑Sensitivity to proarrhythmic drugs | ||||
| A561P | 120 | ↓repolarzation reserve | ||||
| LQT3 | SCN5A | F1473C | 264 | Defective Na+ channel caused by deficiency in open-state inactivation of the Na+ channel | ||
| V1763M | 172 | |||||
| V240M | 67 | Enhanced late Na+ channel current (INaL) | ||||
| R535Q | ||||||
| 1644H | 175 | Delayed repolarization and prolonged APD | ||||
| CPVT1 | RYR2 | F2483I | 68 | ↑Diastolic [Ca2+] | ||
| 322 | ↓SR Ca2+content, indicating Ca2+ leakage | |||||
| S406L | 121 | ↑Frequency and duraton of elemantary Ca2+ release events (sparks) | ||||
| M4109R | 109 | |||||
| P2328S | 142 | Arrhy thmias characterized by DADs, broad and double-humped transists | ||||
| Q2311D | 54 | ↑Senstivity to proarrhythmic drugs | ||||
| R420Q | 206 | Immature ultrastructural features | ||||
| CPVT2 | CASQ2 | D307H | 206 | ↑Diastolic [Ca2+] | ||
| Oscillatory arrhythmic prepotentials, DADs | ||||||
| 207 | Myofibrillar disarray, ↑SR cisternae size, ↑caveolae number | |||||
| TS | CACNA1C | G406R | 312 | Irregular contractility and electrical activity, ↑APD | ||
| ↑Ca2+ influx | ||||||
| Cardiomyopathies | DCM | TNNT2 | R173W | 254 | Abnormal Ca2+ regulation, ↓contractility | |
| 301 | Myofibrillar disarray- | |||||
| RBM20 | R636S | 304 | ||||
| LMNA/C | R225X | 243 | ↑Nuclear blebbing and micronucleation | |||
| ↑Nuclear senescence and apoptosis | ||||||
| DES | A285V | 275 | Abnormal DES aggregations | |||
| ↓ Max rate of Ca2+ re-uptake and ↓beating rate | ||||||
| ↓Tolerance to inotropic stress | ||||||
| HCM | MYH7 | R663H | 147 | ↑Cellular size and sarcomere disorganization | ||
| R442G | 89 | Contractile arrhythmias | ||||
| MYBPC3 | G999-Q1004del | 262 | Dysregulation of Ca2+ cycling and ↑[Ca2+]i | |||
| FXN | Silencing | 153 | FRDA-associated HCM | |||
| ↑Rate of iron accumulation | ||||||
| ↓Ca2+ uptake and release kinetics | ||||||
| Disorganized and fragmented mitochondrial network | ||||||
| ↑ROS accumulation | ||||||
| LS | PTPN11 | T468M- | 31 | ↑Nuclear NFATC4 localization | ||
| 163 | ↑Expression of genes associated with cardiac hypertrophy | |||||
| A324fs335X | 32 | ↑Lipogenesis and apoptosis | ||||
| ARVD | PKP2 | c.2484C>T | 134 | ↓PKP2 and ↑PPAR-γ gene expression | ||
| c.2013delC | ↓PKP2, plakoglobin, and Cx43 protein density | |||||
| c.1841T>C | 170 | ↓β-Catenin activity | ||||
| Desmosome disorganization | ||||||
| DMD | DMD | exon 45-52del | 164 | Dystrophin deficiency | ||
| ↑Levels of resting Ca2+ | ||||||
| Mitochondrial damage and ↑apoptosis | ||||||
| Structural | HLHS | Not identified | Not identified | 115 | ↓Ability for cardiac differentiation | |
| 73 | ↓Myofibrillar organization | |||||
| ↑Fetal gene expression pattern | ||||||
| Calcium transient and electrophysiological abnormalities | ||||||
| Metabolic | ALHD deficiency | ALDH2 | E487K | 63 | ↑Levels of ROS and toxic aldehydes | |
| ↑Cell cycle arrest and activation of apoptotic signaling | ||||||
| BTHS | TAZ | c.517delG c.517ins | 289 | ↑Levels of ROS, ↓mitochondrial function | ||
| ↑Sparse and irregular sarcomeres, weak contractility | ||||||
| Pompe disease | GAA | D645E | 101 | |||
| exon 18del 1441delT | 227 | ↑Levels of glycogen, defective respiration | ||||
| Deficit of Golgi-based protein glycosylation | ||||||
| c.796C>T c.1316T>A | 233 | Ultrastructural aberrances, lysosomal enlargement | ||||
| Engineered | Arrhythmias | LQT1 | KCNQ1 | R190Q | 290 | Protein trafficking defects |
| G269S | ↑APD in atrial and ventricular CMs | |||||
| G345E | Severe ↓ or absence of IKs (LQT1) or IKr (LQT2) | |||||
| LQT2 | KCNH2 | A614V | Arrhythmias characterized by EADs | |||
| N996I | 13 | |||||
| Cardiomyopathies | DCM | PLN | R14del corrected to WT | 130 | Correction of: | |
| Ca2+ handling abnormalities | ||||||
| Electrical instability | ||||||
| Abnormal cytoplasmic distribution of PLN protein | ||||||
| ↑Expression cardiac hypertrophy molecular markers | ||||||
| TTN | W976Rfs A22352fs P22582fs | 93 | ↓Contractile performance due to A-band truncations | |||
| Sarcomere insufficiency | ||||||
| Impaired responses to mechanical and β-adrenergic stress | ||||||
| Attenuated growth factor and cell signaling activation | ||||||
| Metabolic | BTHS | TAZ | c.517delG c.517ins | 289 | ↑Levels of ROS, ↓mitochondrial function | |
| Sparse and irregular sarcomeres, weak contractility |
Together, Table 3 and 4 provide a detailed outline of hiPSC-based models of cardiac disease published to date, with correlation to the gDNA mutations studies, and the key phenotypes observed for each disorder. APD, action potential duration; FPD; field potential duration; ↑, increased; ↓, decreased; EAD, early afterdepolarization; DAD, delayed afterdepolarization; hiPSC, human induced pluripotent stem cell; CMs, cardiomyocytes; SM, small molecule; GF, growth factor; SR, sarcoplasmic reticulum; VPA, valproic acid; ET-1, ETA-b, endothelin receptor type A blocker; ROS, reactive oxygen species; CDI, Cellular Dynamics International; LQT1, 2, 3, long-QT syndrome type 1, 2, 3; JLNS, Jervell and Lange-Nielsen syndrome;CPVT1, 2, catecholaminergic polymorphic ventricular tachycardia type 1, 2; TS, Timothy syndrome; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; FRDA, Friedreich's ataxia; DFP, deferiprone; LS, LEOPARD syndrome; ARVD, arrhythmogenic right ventricular dysplasia; DMD, Duchenne muscular dystrophy; HLHS, hypoplastic left heart syndrome; BTHS, Barth syndrome.